Role of NUB1 in inclusion body formation in synucleinopathies

在人路易体病（LBD）中，抗pk α-突触核蛋白沉积于路易体和路易神经突，以及海马、颞叶皮层和黑质等不同脑区突触前。生化分析显示，Tg小鼠和人LBD的突触前部分检测到pk抗性α-突触核蛋白。我们进一步证明，在LBD患者的大脑中，NUB1在海马、大脑新皮层和黑质的突触前积聚，而pk抗性α-突触核蛋白沉积在这些突触前。内源性NUB1在表达A53T突变的人α-synuclein的Tg小鼠的突触前也积累了耐pk α-synuclein。免疫电镜显示NUB1定位于突触前神经末梢，未见异常纤维。生化分析表明，在LBD患者的大脑中，NUB1与α-突触核蛋白异常共存。这些发现提示NUB1与异常α-突触核蛋白一起参与了LBD的发病过程。

In human Lewy body disease (LBD), PK-resistant α-synuclein was deposited in Lewy bodies and Lewy neurites, as well as in the presynapses in distinct brain regions, including the hippocampus, temporal cortex and substantia nigra. Biochemical analysis revealed that PK-resistant α-synuclein was detected in the presynaptic fraction in Tg mice and human LBD. We further demonstrated that, in the brains of patients with LBD, NUB1 accumulates in the presynapses in the hippocampus, cerebral neocortex, and substantia nigra in which PK-resistant α-synuclein is deposited. Endogenous NUB1 also accumulated with PK-resistant α-synuclein in the presynapses of Tg mice that express human α-synuclein with an A53T mutation. Immunoelectron microscopy showed that NUB1 was localized to presynaptic nerve terminals where no abnormal filaments were seen. Biochemical analyses showed that NUB1 coexists with abnormal α-synuclein in the brains of LBD patients. These findings suggest that NUB1 along with abnormal α-synuclein is involved in the pathogenesis of LBD.